CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`022410Orig1s000
`
`
`
`MEDICAL REVIEW(S)
`
`
`
`
`
`
`
`
`
`
`

`

` FDA CENTER FOR DRUG EVALUATION AND RESEARCH
`
`DIVISION OF ANESTHESIA, ANALGESIA, AND RHEUMATOLOGY PRODUCTS
`
`
`
`
`
`Summary Review for Regulatory Action
`
`
`August 21, 2009
`Bob A. Rappaport, M.D.
`Director
`Division of Anesthesia, Analgesia and Rheumatology
`Products
`Division Director Summary Review
`22-410
`Reckitt Benckiser
`October 21, 2008
`August 21, 2009
`Suboxone (Buprenorphine/naloxone) sublingual film
`
`Sublingual films
`2 mg/0.5 mg and 8 mg/2 mg
`For the maintenance treatment of opioid dependence
`
`
`Complete Response
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Date
`From
`
`Subject
`NDA #
`Applicant Name
`Date of Submission
`PDUFA Goal Date
`Proprietary Name /
`Established (USAN) Name
`Dosage Forms / Strength
`
`Proposed Indication
`
`Action:
`
`
`
`
`
`
`
`
`
`
`(b) (4)
`
`

`

`
`
`
`Material Reviewed/Consulted
`OND Action Package, including:
`Elizabeth M. Kilgore, M.D.; Celia Winchell, M.D.
`Medical Officer Review
`N/A.
`Statistical Review
`Pharmacology Toxicology Review Elizabeth A. Bolan, Ph.D. ; R. Daniel Mellon, Ph.D.
`CMC Review
`Xavier Ysern, Ph.D.; Ali Al-Hakim, Ph.D.
`Microbiology Review
`N/A
`Clinical Pharmacology Review
`Sheetal Agarwal, Ph.D.; Suresh Doddapaneni, Ph.D.
`DDDP
`Fred Hyman, D.D.S., M.P.H.; John Kelsey, D.D.S., M.B.A.;
`Susan Walker, M.D.
`Susan Leibenhaut, M.D.; Constance Lewin, M.D.
`Jian Ping, M.D., Ph.D.; Lori A. Love, M.D. Ph.D.; Michael
`Klein, Ph.D.
`Celia Winchell, M.D.
`Zachary Oleszczuk, Pharm.D; Kellie Taylor, Pharm.D.;
`Denise Toyer, Pharm.D.; Carol Holquist, R.Ph.
`
`DSI
`CSS
`
`CDTL Review
`OSE/DMEPA
`
`OND=Office of New Drugs
`OSE= Office of Surveillance and Epidemiology
`DDDP=Division of Dermatology and Dental Products
`DMEPA=Division of Medication Error Prevention and Analysis
`DSI=Division of Scientific Investigations
`CSS=Controlled Substance Staff
`CDTL=Cross-Discipline Team Leader
`
`
`1. Introduction
`
`
`Reckitt Benckiser has submitted this application for a line extension of and as an alternative to
`their Suboxone tablets which were approved in 2002. This new formulation contains
`buprenorphine and naloxone in a new delivery system, sublingual strips. The dosage strengths
`for these strips, buprenorphine 2 mg/naloxone 0.5 mg and buprenorphine 8 mg/naloxone 2 mg,
`are the same as the approved tablets. The sponsor purportedly created this formulation to
`minimize abuse and misuse, including unintended exposures in children, in addition to
`increasing patient compliance, minimizing counterfeiting, minimizing illegal use and
`diversion, and decreasing product damage during transport and storage compared to the
`sublingual tablets. These goals were based on the use of unit dose packaging and child-
`resistant packaging with improved coding. Support for the efficacy and safety of this product
`rests primarily on data from Phase 1 pharmacokinetic studies and reference to the sponsor’s
`NDAs for Suboxone and Subutex.
`2. Background
`
`
`Buprenorphine is an opioid partial agonist which has been marketed as an injectable analgesic
`since 1982. Subutex (buprenorphine alone) and Suboxone were approved in 2002 for the
`treatment of opioid dependence. These products may only be prescribed by health care
`NDA 22-410 Suboxone (buprenorphine/naloxone) sublingual film
`Division Director Summary Review for Regulatory Action
`August 21, 2009
`
`2
`
`

`

`professionals who have fulfilled certain training requirements defined in the Drug Abuse
`Treatment Act of 2002, which also limits the number of patients for whom a specific health
`care professional or group practice may prescribe these products. Due to its pharmacological
`properties, buprenorphine, with or without naloxone, has been thought to be useful only in
`patients with mild to moderate degrees of opioid dependence. Methadone remains the
`treatment of choice for patients with more severe forms of opioid addiction.
`
`Recent data has shown increasing rates of abuse and diversion of Subutex and Suboxone.
`There is also an unexpectedly high rate of accidental exposure to children, thought to be due to
`the social dysfunction found in the homes of many opioid addicts. However, the number of
`deaths due to these accidental exposures has been low, again possibly due to the
`pharmacological properties of the drug.
`
`The main concerns raised by the review team in regard to this new product are the need for an
`adequate REMS to mitigate the risks of abuse and accidental exposures to children, the need
`for finalization of the ongoing Subutex/Suboxone post-marketing study on hepatotoxicity, and
`better characterization of the mucosal safety of this product. While the clinical review team
`has determined that the hepatotoxicity study and the collection of additional data to support
`mucosal safety may be completed post-marketing, the REMS submitted by the sponsor in this
`application is not acceptable and, therefore, the application cannot be approved at this time.
`
`3. CMC
`
`
`The product is formulated as a sublingually applied film which hydrates to a gel form within
`about 30 seconds after application to the oral mucosa. The gel then erodes over approximately
`three minutes releasing the active components. A process impurity,
`,
`
`was noted to have a structural alert for mutagenicity due to an
`functionality. An Ames test of this impurity was negative, but an in vitro cytogenetic assay in
`human lymphocytes showed it to be clastogenic at high dose levels. The sponsor has agreed to
`a specification limit reduction that is acceptable to the CMC and Pharmacology/Toxicology
`review teams.
`
`The two dosage strengths of this product are produced from separate film formulations. The
`2-mg/0.5-mg strength is produced from a low-strength formulation and the 8-mg/2-mg
`strength is produced form a high-strength formulation. Three different doses made from the
`high-strength formulation were used in the clinical studies, 12 mg/3 mg, 16 mg/4 mg, and the
`to-be-marketed 8 mg/2 mg.
`
` However, as Dr. Winchell notes on page 7 of her review,
`
`
`
`
`
`All manufacturing, testing and packaging facilities have been inspected. A twelve-month
`expiration period is supported by the submitted stability data.
`
`NDA 22-410 Suboxone (buprenorphine/naloxone) sublingual film
`Division Director Summary Review for Regulatory Action
`August 21, 2009
`
`
`
`
`
`
`
`
`3
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`Three concerns were addressed by the pharmacology/toxicology review team:
`
`
`4. Nonclinical Pharmacology/Toxicology
`
`: see discussion
`
`1) Specifications for the clastogenic impurity
`under Section 3.
`2) In vitro studies conducted by the sponsor to assess the interaction of buprenorphine and
`its metabolite norbuprenorphine with several cytochrome P450 enzymes and to assess
`binding of buprenorphine and norbuprenorphine to benzodiazepine receptors due to the
`apparent increased toxicity noted in the clinical setting when Subutex or Suboxone are
`taken concomitantly with benzodiazepines. While there was some inhibition of
`cytochrome P450 enzymes at micromolar levels, the plasma concentrations of
`buprenorphine in the therapeutic range are unlikely to cause clinically significant
`inhibition of these enzymes. Neither buprenorphine nor norbuprenorphine were found
`to bind to either central or peripheral benzodiazepine receptors.
`3) Benign Leydig cell adenomas were observed in a two-year carcinogenicity study of
`Suboxone in rats. Leydig cell adenomas were seen in a prior carcinogenicity study of
`buprenorphine alone in rats, but a mouse study was negative. These findings will be
`discussed in the product labeling.
`5. Clinical Pharmacology/Biopharmaceutics
`
`
`
`
`
`
`The following is reproduced form page 11 of Dr. Winchell’s review:
`
`
`This overview of buprenorphine and buprenorphine/naloxone clinical pharmacology is taken
`largely from the approved labeling for NDA 20-723 and 20-733.
`Pharmacokinetics of buprenorphine and naloxone (as Suboxone) show wide inter-patient
`variability in the sublingual absorption of buprenorphine and naloxone, but within subjects the
`variability is low. Both Cmax and AUC of buprenorphine show dose linearity in the range of 4 to
`16 mg, but not dose proportionality. The table below from the labeling for Suboxone and Subutex
`shows the PK parameters. Buprenorphine has a mean elimination half-life of 37 hours; naloxone
`has a half-life of 1.1 hours. Naloxone does not affect the PK
`
`Pharmacokinetic parameters of buprenorphine after the administration of 4 mg, 8mg, and
`16 mg Suboxone doses and 16mg Subutex dose (mean (%CV)).
`Pharmacokinetic
`Suboxone 4
`Suboxone 8
`Parameter
`mg
`mg
`1.84 (39)
`3.0 (51)
`Cmax, ng/mL
`12.52 (35)
`20.22 (43)
`AUC0-48,
`hour.ng/mL
`
`Buprenorphine is approximately 96% protein bound, primarily to alpha and beta globulin.
`Naloxone is approximately 45% protein bound, primarily to albumin.
`
`Buprenorphine undergoes both N-dealkylation to norbuprenorphine and glucuronidation. The N-
`dealkylation pathway is mediated by cytochrome P-450 3A4 isozyme. Norbuprenorphine, an
`active metabolite, can further undergo glucuronidation. Cytochrome P-450 3A4 (CYP3A4)
`inhibitors may increase plasma concentrations of buprenorphine.
`NDA 22-410 Suboxone (buprenorphine/naloxone) sublingual film
`Division Director Summary Review for Regulatory Action
`August 21, 2009
`
`Suboxone16
`mg
`5.95 (38)
`34.89 (33)
`
`Subutex 16
`mg
`5.47 (23)
`32.63 (25)
`
`4
`
`(b) (4)
`
`

`

`Geometric
`Estimate
`
`0.78 + 0.32
`
`0.95 + 0.27
`
` 121.66
`
`7.65 + 2.65
`
`8.65 + 2.85
`
` 114.22
`
`Bup Cmax
`(ng/mL)
`Bup AUC inf
`(ng*h/mL)
`Nal Cmax
`(pg/mL)
`Nal AUC inf
`(pg*h/mL)
`
`Study 20-272-SA: 4/1 mg (2 x 2/0.5 mg) strips vs. tabs
`SL tab
`SL strip
`Geometric
`
`Estimate
`
`51.3 + 21.1
`
`54.1 + 23.0
`
` 104.01
`
`124.2 + 52.5 137.3 + 43.1
`
` 107.28
`
`90%
`Confidence
`Interval
`112.62 – 131.43
`
`106.65 – 122.32
`
`95.79 – 112.93
`
`96.98 – 118.69
`
`90%
`Confidence
`Interval
`94.58 – 115.69
`
`
`Naloxone undergoes direct glucuronidation to naloxone 3-glucuronide as well as N-dealkylation,
`and reduction of the 6-oxo group. Buprenorphine is eliminated in urine (30%, primarily
`conjugated) and feces (69%, primarily free buprenorphine and norbuprenorphine).
`
`The effect of hepatic impairment on the pharmacokinetics of buprenorphine and naloxone is
`unknown. Since both drugs are extensively metabolized, the plasma levels will be expected to be
`higher in patients with moderate and severe hepatic impairment. However, it is not known
`whether both drugs are affected to the same degree. Renal impairment does not affect
`buprenorphine PK. The effects of renal failure on naloxone PK are unknown.
`
`
`Bioequivalence of the strips compared to the tablets was evaluated in seven studies. The key
`results from those studies are reproduced below in tables from Dr. Winchell’s review, pages
`13 through 15; values outside of the standard bioequivalence limits of 80 to 120% are shown
`in italics:
`
`Study 20-250-SA: 2/0.5 mg strips vs. tabs
`SL tab
`SL strip
`
`
`Bup Cmax
`(ng/mL)
`Bup AUC inf
`(ng*h/mL)
`Nal Cmax
`(pg/mL)
`Nal AUC inf
`(pg*h/mL)
`
`
`1.34 + 0.57
`
`1.40 + 0.68
`
` 104.61
`
`12.46 + 4.64
`
`13.71 + 5.88
`
` 104.55
`
`96.42 – 113.37
`
`70.8 + 34.7
`
`69.8 + 37.8
`
` 100.86
`
`90.95 – 111.84
`
`204.6 + 114.9 204.3 + 108.4 106.48
`
`93.26 – 121.58
`
`NDA 22-410 Suboxone (buprenorphine/naloxone) sublingual film
`Division Director Summary Review for Regulatory Action
`August 21, 2009
`
`5
`
`

`

`Study 20-273-SA: 8/2 mg strips vs. tabs1
`SL tab
`SL strip
`
`
`Geometric
`Estimate
`
`2.58 + 1.10
`
`3.37 + 1.80
`
` 127.8
`
`90%
`Confidence
`Interval
`116.11 – 140.66
`
`25.31 + 9.50
`
`30.45 + 13.03 119.51
`
`110.28 – 129.51
`
`135.0 + 57.3
`
`193.0 + 91.2
`
` 141.04
`
`126.87 – 156.80
`
`374.6 + 132.8 480.8 + 201.0 121.19
`
`108.44 – 135.44
`
`Bup Cmax
`(ng/mL)
`Bup AUC inf
`(ng*h/mL)
`Nal Cmax
`(pg/mL)
`Nal AUC inf
`(pg*h/mL)
`
`Study 10033995: 12/3 mg (1 x 8/2 mg + 2 x 2/0.5 mg) strips vs. tabs
`SL tab
`SL strip
`Geometric
`90%
`
`Estimate
`Confidence
`Interval
`106.44 – 124.35
`
`37.11 + 14.14 40.50 + 15.93 111.21
`
`105.62 – 117.09
`
`170.0 + 77.6
`
`207.0 + 143.0 117.24
`
`106.80 – 128.71
`
`524.0 + 253.6 582.7 + 324.9 110.47
`
`102.90 – 118.60
`
`NDA 22-410 Suboxone (buprenorphine/naloxone) sublingual film
`Division Director Summary Review for Regulatory Action
`August 21, 2009
`
`6
`
`3.44 + 1.53
`
`4.05 + 2.63
`
` 115.05
`
`Bup Cmax
`(ng/mL)
`Bup AUC inf
`(ng*h/mL)
`Nal Cmax
`(pg/mL)
`Nal AUC inf
`(pg*h/mL)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`1 DSI concluded that “Accuracy of the reported naloxone concentrations for subjects 407 (Period 2) and 443 (all periods) has
`not been assured due to unresolved chromatographic interference in at least half the reportable naloxone values in each period.
`The naloxone data for these periods should be omitted and bioequivalence should be re-evaluated.” A reevaluation was
`performed by Dr. Agarwal. However, because bioequivalence was not previously established for naloxone in this study, the
`effect of this reanalysis would be unlikely to change the conclusions about the application. [Indeed, Dr. Agarwal’s
`reevaluation did demonstrate that the data remained supportive in spite of the DSI findings.]
`
`
`

`

`
`Study 20-A90-AU: 16/4 mg strips vs. tabs
`SL tab
`SL strip
`
`
`Geometric
`Estimate
`
`4.51 + 1.51
`
`5.47 + 1.99
`
` 133.64
`
`90%
`Confidence
`Interval
`117.52 – 151.98
`
`Bup Cmax
`(ng/mL)
`Bup AUC inf
`(ng*h/mL)
`Nal Cmax
`(pg/mL)
`Nal AUC inf
`(pg*h/mL)
`
`Study 20-291-SA: Dose proportionality of the 2/0.5, 2 x 2/0.5, 8/2, 12/3 and 16/4 mg strips
`Buprenorphine
`
`2/0.5
`
`47.31 + 13.81 58.53 + 20.59 132.50
`
`120.63 – 145.54
`
`259.0 + 200.0 324.0 + 231.0 143.79
`
`116.86 – 176.92
`
`677.7 + 366.4 930.4 + 421.3 137.71
`
`121.19 – 156.49
`
`2*2/0.5
`
`8/2
`
`12/3
`
`16/4
`
`Cmax
`(ng/mL)
`AUClast
`(hr*ng/mL)
`AUCinf
`(hr*ng/mL)
`
`Naloxone
`
`
`1.07
`
`7.18
`
`8.43
`
`1.66
`
`13.42
`
`14.62
`
`3.55
`
`4.80
`
`6.05
`
`28.71
`
`39.86
`
`50.32
`
`30.66
`
`41.74
`
`53.40
`
`2/0.5
`
`2*2/0.5
`
`8/2
`
`12/3
`
`16/4
`
`48.5
`
`72.8
`
`193
`
`286
`
`401
`
`100.6
`
`164.1
`
`442.9
`
`647.5
`
`937.9
`
`105.1
`
`171.0
`
`454.8
`
`665.1
`
`958.4
`
`Cmax
`(pg/mL)
`AUClast
`(hr*pg/mL)
`AUCinf
`(hr*pg/mL)
`
`
`There are “high-side” failures for all comparisons, most prominently for the higher strength
`strips. However, there were no new safety concerns noted in the clinical database for subjects
`using these strips and the safety of doses of up to 24 mg/day of the Suboxone tablets is
`supported by the application for that product, a reference listed drug for this application.
`
`
`
`
`
`NDA 22-410 Suboxone (buprenorphine/naloxone) sublingual film
`Division Director Summary Review for Regulatory Action
`August 21, 2009
`
`7
`
`

`

`
` 6. Clinical Microbiology
`
`Not applicable.
`
`7. Clinical/Statistical-Efficacy
`
`
`No new efficacy data was submitted in support of this application. The sponsor is depending
`on their 505(b)(2) reference which is acceptable.
`
`8. Safety
`
`
`There were 126 subjects exposed for 12 weeks to any dose of the study drug. Fewer than 80
`of those subjects were dosed within the labeled range of 12 to 16 mg; however, patients can be
`maintained on lower doses of the tablets, so this data base is acceptable. Dr. Winchell raises a
`concern regarding the fact that the subjects in the clinical studies were prescribed and/or self
`administered drug in multiple divided doses, in contrast to the labeled single daily dosing
`regimen. A survey by the sponsor also found this practice occurring with Suboxone
`prescribing and use. Dr. Winchell notes that, single daily dosing is thought to assist in
`extinguishing the behavior of self-administration that occurs in addiction and that, indeed,
`there is a substantial literature advocating dosing on a less than daily basis for this reason. The
`REMS for this product will need to fully address appropriate dosing for prescribers and
`include statements related to proper use in the MedGuide for patients.
`
`There were no serious or unexpected safety signals found in the clinical data base for the
`studies of this new formulation. However, oral mucosal irritation did appear to occur with
`much greater frequency compared to the tablet formulation. While the main safety study for
`this application did not identify any treatment-related safety issues related to the mouth, Dr.
`Winchell notes that that study may not have been appropriately conducted to do so. In
`addition, the clinical pharmacology studies and a small, inpatient induction study did suggest
`the strips may be associated with mild oral irritation. Another possible complication related to
`assessing the oral tolerability of the product is that the strips were not used in the clinical study
`in the manner outlined in the proposed product label. However, based on his review of the
`studies, Dr. Hyman drew the following conclusions (pages 5 and 6 of this review):
`
`
`It is the recommendation of this reviewer that the difference between the sponsor’s planned application
` versus the actual application in the clinical trials to the floor of the
`mouth, under the tongue will not invalidate the safety results of the clinical trials. However, the
`printed directions for use should reflect the actual placement during the clinical trials. In particular, the
`illustration in the Medication Guide section of the labeling should be replaced with one that reflects the
`actual use during the clinical trials; also the description of placement for the second FS as
`
`
` should be avoided. Should the sponsor wish to label the drug to
` clinical studies should be repeated in that manner to test for ease of use, and any
`oral irritation that could result from this application.
`
`
`
`The sponsor has agreed to change the labeled administration instructions to appropriately
`reflect how the product was used in the clinical studies.
`NDA 22-410 Suboxone (buprenorphine/naloxone) sublingual film
`Division Director Summary Review for Regulatory Action
`August 21, 2009
`
`8
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`The clinical review team had raised concerns regarding precipitated withdrawal in the opioid
`dependent patients who would be treated with this product. Although Dr. Winchell expressed
`some discomfort with the one study specifically designed to evaluate this potential, she
`concluded that the results were generally not concerning. The incidence of withdrawal
`symptoms in the overall database was no higher than would be expected in this population.
`
`Hepatic toxicity has been seen in the post-marketing data for Suboxone. While no new or
`increased signal was noted in the database for this product, Dr. Winchell has recommended
`that the post-marketing study commitment to evaluate the comparative effects of
`buprenorphine and methadone on the liver should be reiterated, but this time as a post-
`marketing requirement. I concur with this recommendation.
`
`9. Advisory Committee Meeting
`
`
`The review team determined that an advisory committee meeting was unnecessary for this new
`formulation of buprenorphine/naloxone as there were no clinically serious new or unexpected
`safety concerns specific to this product.
`
`10.
`Pediatrics
`
`
`This product is exempt from the pediatric study requirements authorized by PREA as the
`sponsor received orphan designation for the active moiety of buprenorphine, with or without
`naloxone, for the treatment of opioid addiction.
`
`11.
`Other Relevant Regulatory Issues
`
`
`There are no other outstanding regulatory issues.
`
`12.
`Labeling
`
`
`The labeling has been provisionally revised from the reference listed drug's label in several
`ways. It emphasizes more strongly the abuse potential of the drug and the risk of accidental
`pediatric exposure and includes more explicit recommendations on clinical management in the
`dosing and administration section. A final label will require further discussion with the
`sponsor and include appropriate references to the product’s REMS.
`
`
`
`
`
`
`
`
`
`
`NDA 22-410 Suboxone (buprenorphine/naloxone) sublingual film
`Division Director Summary Review for Regulatory Action
`August 21, 2009
`
`9
`
`

`

`
`
`
`
`
`
`
`
`
`
`13.
`
`Decision/Action/Risk Benefit Assessment
`• Regulatory Action
`
`Complete Response
`
`• Risk Benefit Assessment
`
`
`The sponsor has demonstrated that this new formulation of buprenorphine and
`naloxone is safe and effective when used according to the labeled instructions,
`and that the product quality is acceptable. However, they will need to provide
`an adequate REMS to address the Agency’s concerns regarding misuse and
`abuse of the product and, therefore, I am unable to approve the application at
`this time.
`
`• Required Post-marketing Risk Evaluation and Mitigation Strategy
`
`In order to assure that the benefits of this product outweigh the risks of abuse,
`misuse and accidental pediatric exposure, the Agency has determined that the
`product must have a REMS comprised of a MedGuide, an Element to Assure
`Safe Use (ETASU), and a timetable for submission of assessments of the
`REMS. The ETASU falls under section 505-1(f)(3)(E) of the FDCA and is
`intended to ensure that 1) each patient is receiving the psychosocial support
`necessary for safe and effective use buprenorphine, 2) each patient adheres to
`the conditions of safe use explained to him/her, and 3) each patient is using
`Suboxone sublingual film appropriately and making adequate progress towards
`treatment goals.
`.
`• Required Post-marketing Study Requirements
`
`As we are unable to approve this application at this time, we will continue to
`work with the sponsor to assure completion of their ongoing study designed to
`evaluate the comparative effects of buprenorphine and methadone on the liver.
`Should that study not be completed at the time this application is ready for
`approval, we will change it from a post-marketing commitment to a post-
`marketing requirement.
`
`
`
`NDA 22-410 Suboxone (buprenorphine/naloxone) sublingual film
`Division Director Summary Review for Regulatory Action
`August 21, 2009
`
`10
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`BOB A RAPPAPORT
`08/21/2009
`
`

`

`
`Date
`From
`Subject
`
`NDA #
`Applicant
`Date of Submission
`
`PDUFA Goal Date
`Proprietary Name /
`Established (USAN) names
`
`Dosage forms / Strength
`
`Proposed Indication(s)
`
`Addendum to Cross-Discipline Team Leader Review
`
`8/10/09
`Celia Winchell, M.D., Clinical Team Leader
`Addendum to Cross-Discipline Team Leader Review:
`Resolution of Concerns Regarding Methods of
`Administration of the Proposed Product
`22-410
`Reckitt Benckiser
`Letter Date: 10/20/08
`Stamp Date: 10/21/08
`8/21/09
`<TRADENAME TBA>
`(buprenorphine and naloxone) sublingual film
`2 mg/0.5 mg and 8 mg/2 mg
`Buprenorphine 2 mg with Naloxone 0.5 mg
`Buprenorphine 8 mg with Naloxone 2 mg
`Maintenance Treatment of Opioid Dependence
`
`
`
`
`
`At the time my Cross-Disciplinary Team Leader Review was finalized (7/10/09, to meet
`Good Review Management Practices timetable requirements), there was a new issue
`which was described as unresolved. This memo documents the resolution of that issue.
`
`At that time, it had recently come to our attention that there were potentially clinically
`significant discrepancies among the sponsor's recommended method of administration (in
`proposed labeling), the method of administration in the clinical pharmacology program,
`and the method of administration in the clinical safety study. The patient labeling
`submitted in late June contained an illustration making it clear that the product was to be
`applied
`. None of the
`directions in the clinical studies appear to have communicated this clearly. The clinical
`pharmacology studies used complicated wording that was difficult to interpret but did not
`convey the concept illustrated in the proposed labeling; the clinical safety study used
`directions which implied that the product should be placed on the floor of the mouth.
`
`We obtained information from Reckitt Benckiser regarding how the products were
`actually administered in the clinical studies. Using photographs illustrating the oral
`cavity, the investigators indicated the location that the study drug was placed by their
`subjects. Although Reckitt Benckiser’s interpretation of the photographs was
`
`
`(b) (4)
`
`(b)
`(4)
`
`(b) (4)
`
`

`

`
`However, the interpretation of the review staff of the photographs sent was that the
`investigators indicated that the product was placed in the floor of the mouth.
`
`We requested that the Division of Dermatology and Dental Products (DDDP) provide an
`assessment of the potential impact of various administration methods, and an opinion on
`whether the data from the studies provides support for the use of the product as proposed
`in labeling. Dr. Frederick Hyman of DDDP noted that
`[A]ccording to the descriptions of the placement as provided in the protocols, as well as the
`photographs that were taken during the trials that showed the placement, the strips were placed on
`the floor of the mouth. The sponsor’s proposed labeling includes
`
`
`
` Instead, the instructions should reflect the actual
`
`
`
`use during the trial.
`
`
`
` …
`
`
`It is the recommendation of this reviewer that the difference between the sponsor’s planned
`application
` versus the actual application in the clinical trials to the
`floor of the mouth, under the tongue will not invalidate the safety results of the clinical trials.
`However, the printed directions for use should reflect the actual placement during the clinical
`trials.
`
`
`The Clinical Pharmacology team was also been asked to comment on the potential impact
`of different administration methods on the pharmacokinetics, to determine whether the
`PK studies were conducted in a manner that provides information about the PK when the
`product is used as proposed in labeling. Dr. Sheetal Agarwal provided the following
`comments.
`As a matter of general understanding and use of terminology, sublingual administration means that
`the drug product is placed underneath the tongue. In this case, the product will rest on the floor of
`the mouth
`
` The sublingual film strips are formulated to dissolve rapidly. Upon contact
`with the oral mucosa, the strips hydrate rapidly forming a hydrophilic gel which then erodes in a
`period of about three minutes. So, dissolution is not a rate limiting step with the sublingual strips
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b)
`
`
`
`

`

`and the exact placement of the strip and any folding or bending of the strips should not
`significantly alter the dissolution rate…. Although not sought for approval, sponsor tested the
`buccal mode of administration as well in several of the PK studies. Although not reviewed in
`detail, a quick overview of the studies showed …these two routes of administration yielded similar
`bioavailability [lending] further comfort that any bioavailability differences resulting from the
`potentially different ways in which the sublingual strips may have been used in the NDA database
`may not be clinically significant.
`
`
`
`
`
`
`
`
`
`
`
`
` No diagram or illustration is
`likely to be required to help patients understand this placement, it is the placement that
`was actually used in both clinical pharmacology and safety studies, and upon which all of
`the data submitted to this application was based.
`
`Reckitt Benckiser has agreed to amend the directions and proposes the following
`alternative set of directions, which appear basically acceptable but have not yet been
`reviewed by the OSE personnel with expertise in patient communication.
`
`
`
`
`This issue is therefore resolved by the modification of the labeling to match the way the
`product was actually tested.
`
`(b) (4)
`
`(b) (4)
`
`

`

`Linked Applications Submission
`Type/Number
`--------------------
`--------------------
`NDA 22410
`ORIG 1
`
`Sponsor Name
`
`Drug Name / Subject
`
`--------------------
`
`------------------------------------------
`SUBOXONE
`(BUPRENORPHINE/NALOXONE
`)
`
`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`CELIA J WINCHELL
`08/10/2009
`
`

`

`Cross-Discipline Team Leader Review
`
`Cross Discipline Team Leader Review
`
`
`Date
`From
`Subject
`NDA #
`Applicant
`Date of Submission
`
`PDUFA Goal Date
`Proprietary Name /
`Established (USAN) names
`
`Dosage forms / Strength
`
`Proposed Indication(s)
`
`7/10/09
`Celia Winchell, M.D., Clinical Team Leader
`Cross-Discipline Team Leader Review
`22-410
`Reckitt Benckiser
`Letter Date: 10/20/08
`Stamp Date: 10/21/08
`8/21/09
`<TRADENAME TBA>
`(buprenorphine and naloxone) sublingual film
`2 mg/0.5 mg and 8 mg/2 mg
`Buprenorphine 2 mg with Naloxone 0.5 mg
`Buprenorphine 8 mg with Naloxone 2 mg
`Maintenance Treatment of Opioid Dependence (
`
`
`
`
`Complete Response
`Recommended:
`1
`Introduction..........................................................................................................................3
`2 Background..........................................................................................................................4
`3 CMC/Device ........................................................................................................................6
`3.1
`General product quality considerations .......................................................................6
`3.2
`Facilities review/inspection .........................................................................................8
`3.3
`Stability........................................................................................................................8
`3.4
`Other notable issues: Packaging and Labeling Process ...............................................8
`4 Nonclinical Pharmacology/Toxicology ...............................................................................9
`4.1
`Specifications for clastogenic impurity .......................................................................9
`4.2
`In vitro studies..............................................................................................................9
`4.3
`Carcinogenicity............................................................................................................9
`5 Clinical Pharmacology/Biopharmaceutics.........................................................................11
`5.1.1
`General Background ..........................................................................................11
`5.1.2
`Clinical Pharmacology Data Reviewed .............................................................11
`6 Clinical Microbiology........................................................................................................15
`7 Clinical/Statistical- Efficacy..............................................................................................16
`8
`Safety .................................................................................................................................17
`8.1
`Overview....................................................................................................................17
`8.2
`Background................................................................................................................17
`8.3
`Brief Descriptions of Studies Included in Safety Review .........................................18
`8.3.1
`Study RB-US-07-001.........................................................................................18
`8.3.2
`Study RB-US-07002 ..........................................................................................22
`8.3.3
`Clinical Pharmacology Program........................................................................22
`8.4
`Safety Findings ..........................................................................................................23
`8.4.1.1 Deaths ........